As a pediatric geneticist, the P.I. has a keen interest in understanding the molecular pathology of inherited disorders, especially in children. The long term goal is to establish a career in academic medicine, which would allow the PI to study the importance of modifier genes for phenotypic variation in clinically relevant genetic disorders. Current Departmental projects are highly relevant to this proposal and will provide the necessary building blocks for the PI's career development. Hearing loss affects at least 5 percent of the population with the incidence of profound deafness at birth or during early childhood being estimated as about 0.8 per 1000. It is etiologically heterogenous, with genetic factors accounting for half of all cases of profound deafness, 10-20 percent of which are due to a specific hereditary syndrome. Waardenburg syndrome (WS) is a symptom complex that includes deafness, dystopia canthorum, white forelock and heterochromia. We participated in mapping the gene to 2q35 region, the discovery of genetic heterogeneity in WS, and in the demonstration of mutational heterogeneity at the PAX3 locus. The extensive phenotypic variation observed within WS1 families combined with the striking concordance for phenotype in MZ twins strongly suggests that modifier gene(s) contribute to this variability. The present proposes to identify and characterize the gene(s) causing deafness in individuals who have inherited a gene for WS type 1. We have identified 22 WS1 families with a minimum of 2 or more WS1 siblings who are both affected with deafness. This is ideal for mapping modifier gene(s) by an "affecteds" only approach. A two tiered mapping strategy involving a candidate gene search followed by a genome wide scan is proposed. Nonparametric methods of analysis will be used in addition to the traditional parametric approach to extract maximum information from families being studies. We will also further characterize the spectrum of PAX3 mutations in 30 available families with WS1 and study their potential interaction with the modifier gene(s). The successful identification of modifier genes which cause deafness in WS could lead to improved predictive testing.